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1.
Sci Rep ; 11(1): 21348, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34725421

RESUMO

Rare, yet biologically critical, lipids that contain very long chain fatty acids (VLCFA-lipids) are synthesized in the brain by the enzyme ELOVL4. High levels of VLCFA-lipids are toxic to cells and excess VLCFA-lipids are actively removed by ABCD1 in an ATP-dependent manner. Virtually nothing is known about the impact of VLCFA-lipids in neurodegenerative diseases. Here, we investigated the possible role of VLCFA-lipids in frontotemporal dementia (FTD), which is a leading cause of younger-onset dementia. Using quantitative discovery lipidomics, we identified three VLCFA-lipid species that were significantly increased in FTD brain compared to controls, with strong correlations with ELOVL4. Increases in ELOVL4 expression correlated with significant decreases in the membrane-bound synaptophysin in FTD brain. Furthermore, increases in ABCD1 expression correlated with increases in VLCFA-lipids. We uncovered a new pathomechanism that is pertinent to understanding the pathogenesis of FTD.

2.
Ann Palliat Med ; 10(9): 9810-9819, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34628907

RESUMO

BACKGROUND: This study sought to classify the level of quality of life in patients with moderate to severe hand trauma, and explore differences in their potential profile characteristics based on the Patient-Reported Outcomes Measurement Information System (PROMIS). METHODS: This was a survey research. A convenience sampling method was used to investigate 296 patients with moderate to severe hand trauma. A general information questionnaire (which was used to gather general demographic data and disease-related data) and PROMIS-57 were administered form November 2020 to May 2021. A latent profile analysis and Chi square test were conducted to analyze the data. RESULTS: Based on quality of life, patients with moderate to severe hand trauma were divided into the following 3 groups: (I) Group C1: the psychosocial-pain low-impact group (38.9%); (II) Group C2: the psychosocial-moderate-impact severe-pain group (43.9%); and (III) Group C3: the psychosocial-pain high-impact group (17.2%). There were significant differences in the distribution of age, educational level, marital status, occupation, monthly income, medical insurance type, family role, subsequent financial resources, cause of the injury, satisfaction with the appearance of the hand, degree of the injury, and impact of the injury on daily life among patients in the different groups (P<0.05). CONCLUSIONS: The quality of life in patients with moderate to severe hand trauma can be identified to provide precise care.


Assuntos
Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Humanos , Dor , Inquéritos e Questionários
3.
Immunity ; 54(10): 2231-2244.e6, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34555337

RESUMO

RNA interference (RNAi) is the major antiviral mechanism in plants and invertebrates, but the absence of detectable viral (v)siRNAs in mammalian cells upon viral infection has questioned the functional relevance of this pathway in mammalian immunity. We designed a series of peptides specifically targeting enterovirus A71 (EV-A71)-encoded protein 3A, a viral suppressor of RNAi (VSR). These peptides abrogated the VSR function of EV-A71 in infected cells and resulted in the accumulation of vsiRNAs and reduced viral replication. These vsiRNAs were functional, as evidenced by RISC-loading and silencing of target RNAs. The effects of VSR-targeting peptides (VTPs) on infection with EV-A71 as well as another enterovirus, Coxsackievirus-A16, were ablated upon deletion of Dicer1 or AGO2, core components of the RNAi pathway. In vivo, VTP treatment protected mice against lethal EV-A71 challenge, with detectable vsiRNAs. Our findings provide evidence for the functional relevance of RNAi in mammalian immunity and present a therapeutic strategy for infectious disease.


Assuntos
Antivirais/farmacologia , Infecções por Enterovirus/virologia , RNA Viral/antagonistas & inibidores , Animais , Chlorocebus aethiops , Enterovirus Humano A , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos/farmacologia , Interferência de RNA , RNA Interferente Pequeno/antagonistas & inibidores , Células Vero , Replicação Viral/efeitos dos fármacos
4.
Artigo em Inglês | MEDLINE | ID: mdl-34462860

RESUMO

To find out the genuine characteristics of Eucommia ulmoides produced in Guizhou.The habitat, functional characters and the content of medicinal components of Eucommia ulmoides in Guizhou were studied by using the method of sample survey combined with typical survey, related laboratory experiments and quantitative analysis. The results showed that the yield of Eucommia ulmoides plantation in Guizhou was divided into low altitude, low middle and high temperature rain slope latitude mixing, short sunshine hours type(A type), medium altitude, low longitude and latitude, high temperature rain, positive oblique steep slope, medium sunshine hours type (B type), middle altitude, low longitude and latitude, moderate high temperature rain, shady side and sunny side have gentle deflection steep slope, medium sunshine hours type (C type), High altitude, low longitude and latitude, low temperature moderate rain, positive gentle slope, long sunshine hours type (D type); Different types of Eucommia ulmoides plantation, Different habitat quality, B type is intensity karst rocky desertification habitat, A type is potential karst rocky desertification habitat, the C and D types are light and moderate rocky desertification areas, respectively, the species diversity of shrub layer in Eucommia ulmoides plantation was higher in D type and B type, A type and C type followed; There was no significant difference in root carbon content and leaf nitrogen content in 4 types of Eucommia ulmoides plantation, Among the four types of A, B, C, D, there were significant or extremely significant differences in other indexes of plant functional traits; Both genipinic acid and aucubin had the highest content of root bark, followed by trunk bark and lowest leaves, Chlorogenic acid is the opposite, The content of geniposide was higher in trunk bark and lower in root bark and leaves; Genipinic acid is higher in D type, Aucubin is higher in A and D type, Chlorogenic acid has higher leaves content in B type, Geniposide was the highest in trunk bark of D type; The element enrichment coefficient K and Mn leaves are the largest, the largest in trunk bark is Ca and Zn, Fe root bark is the largest; Effects of soil potassium, phosphorus, pH value and bulk weight on the functional traits of Eucommia ulmoides were significant. The contents of medicinal components in root bark, trunk bark, and leaves was influenced by species diversity of shrub layer, The contents of geniposide in root bark, aucubin in root bark and trunk bark, genipinic acid in bark and chlorogenic acid in leaves were particularly affected by soil physical and chemical indexes and metal element contents, The functional traits of Eucommia ulmoides can affect the content of medicinal components in root bark, trunk bark, and leaves, Especially on the root bark, trunk bark, and leaves in the content of aucubin content; The content of medicinal components of Eucommia ulmoides was high and stable. The above research results have important theoretical reference significance for the cultivation of Eucommia ulmoides and the cultivation of target medicinal components and the comprehensive exploitation and utilization of resources.

5.
Front Cell Dev Biol ; 9: 612476, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34295884

RESUMO

Parkinson's disease (PD) is an age-related neurodegenerative disorder affecting millions of people worldwide. The disease is characterized by the progressive loss of dopaminergic neurons and spread of Lewy pathology (α-synuclein aggregates) in the brain but the pathogenesis remains elusive. PD presents substantial clinical and genetic variability. Although its complex etiology and pathogenesis has hampered the breakthrough in targeting disease modification, recent genetic tools advanced our approaches. As such, mitochondrial dysfunction has been identified as a major pathogenic hub for both familial and sporadic PD. In this review, we summarize the effect of mutations in 11 PARK genes (SNCA, PRKN, PINK1, DJ-1, LRRK2, ATP13A2, PLA2G6, FBXO7, VPS35, CHCHD2, and VPS13C) on mitochondrial function as well as their relevance in the formation of Lewy pathology. Overall, these genes play key roles in mitochondrial homeostatic control (biogenesis and mitophagy) and functions (e.g., energy production and oxidative stress), which may crosstalk with the autophagy pathway, induce proinflammatory immune responses, and increase oxidative stress that facilitate the aggregation of α-synuclein. Thus, rectifying mitochondrial dysregulation represents a promising therapeutic approach for neuroprotection in PD.

6.
Mov Disord ; 36(9): 2085-2093, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33899954

RESUMO

BACKGROUND: Pathology in the noradrenergic A6 locus coeruleus has not been compared with more rostral dopaminergic A9 substantia nigra and A10 ventral tegmental area, and cholinergic Ch4 basal nucleus and Ch1/2 septal regions in the same cases of Parkinson's disease (PD). OBJECTIVE: To determine whether there is a gradient of caudal to rostral cell loss in PD. METHODS: Postmortem brains were collected from longitudinally followed donors with PD (n = 14) and aged-matched healthy donors (n = 13), six with restricted brainstem Lewy pathology (RLP), fixed in formalin and serial tissue slabs processed for cell and pathological quantitation. Noradrenergic A6 neurons were assessed and compared with previously published midbrain and basal forebrain data. From these data, regression estimates of pathological onset and progression were determined. RESULTS: Restricted Lewy pathology (RLP) cases had high pathological variability but no significant reduction in neurons. Pathology containing A6 neuron loss started at PD diagnosis and progressed faster (2.4% p.a) than the loss of dopaminergic A9 neurons (2% loss p.a.). Cases with dementia had significantly more pathology in noradrenergic and cholinergic neurons, had greater noradrenergic A6 neuron loss (29% more, progressing at 3.2% p.a.), and a selective loss of lateral A10 nonmelanized dopamine-producing neurons (starting a decade following diagnosis). CONCLUSIONS: These findings show that in the same Parkinson's disease cases cell loss in these neurotransmitter systems does not follow a strict caudal to rostral trajectory and suggests symptom onset may relate to substantial pathology in the noradrenergic A6 locus coeruleus neurons in people with reduced dopamine-producing A9 substantia nigra neurons. © 2021 International Parkinson and Movement Disorder Society.


Assuntos
Doença de Parkinson , Idoso , Neurônios Dopaminérgicos , Humanos , Locus Cerúleo , Prosencéfalo , Substância Negra
7.
Tuberculosis (Edinb) ; 124: 101967, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32745953

RESUMO

In this study, we aimed to assess the performance of Xpert in fresh tissue and formaldehyde-fixed and paraffin embedded (FFPE) specimens from suspected lymphatic tuberculosis for the diagnosis of Mycobacterium tuberculosis (MTB). A total of 52 suspected lymphatic tuberculosis (TB) samples and 10 non-tuberculous lymph nodes samples were collected from outpatients. Using the comprehensive diagnostic criteria as the gold standard, the specificity in fresh and FFPE samples was 100% and the sensitivity was 82.7% and 67.3%, respectively. The majority of fresh tissue specimens had medium and low MTB content, while the low and very low MTB content were noted in 42.9% and 54.3% of FFPE tissue specimens, respectively. There were statistical differences in the MTB content between the two specimen groups detected by Xpert. Three rifampicin-resistant cases in FFPE samples were noted as rifampicin-susceptible in fresh tissue samples. Notably, all three cases with contradictory results of rpoB gene mutation test in fresh and FFPE samples had very low MTB content in FFPE samples. Fresh tissue specimens are more likely to yield Xpert results with high greater MTB content than FFPE specimens from lymphatic TB. The false detection of rpoB mutants is associated with the low bacterial content in the specimens.


Assuntos
Proteínas de Bactérias/genética , Técnicas Bacteriológicas , RNA Polimerases Dirigidas por DNA/genética , Farmacorresistência Bacteriana/genética , Fixadores , Formaldeído , Linfonodos/microbiologia , Mycobacterium tuberculosis/genética , Inclusão em Parafina , Fixação de Tecidos , Tuberculose dos Linfonodos/diagnóstico , Antibióticos Antituberculose/farmacologia , Análise Mutacional de DNA , Humanos , Testes de Sensibilidade Microbiana , Mutação , Mycobacterium tuberculosis/efeitos dos fármacos , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Rifampina/farmacologia , Tuberculose dos Linfonodos/tratamento farmacológico , Tuberculose dos Linfonodos/microbiologia
8.
J Alzheimers Dis ; 77(1): 367-374, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32804130

RESUMO

BACKGROUND: Diabetes may increase the risk of conversion of mild cognitive impairment (MCI) to dementia. Lipid accumulation product (LAP), an index of visceral obesity, has been shown to be a powerful predictor of insulin resistance and type 2 diabetes (T2D). However, little attention has been paid to the relationship between LAP and MCI in T2D. OBJECTIVE: We aimed to investigate the association between the LAP index and MCI in patients with T2D. METHODS: In total, 220 hospitalized patients with T2D, including 113 MCI patients and 107 patients with normal cognition, were enrolled in this cross-sectional study. We collected demographic, anthropometric, and biochemical data on each subject. The LAP index was calculated according to the following formulas: [waist circumference (WC) (cm) - 65]×triglyceride (TG) (mmol/L) for males and [WC (cm) - 58] ×TG (mmol/L) for females. RESULTS: Compared with patients with normal cognition, MCI patients were older and had a higher LAP index, WC, body mass index, and glycosylated hemoglobin A1c level, as well as a lower Montreal Cognitive Assessment score and education level (p < 0.05). After adjusting for confounding factors, LAP index was associated with MCI (OR = 1.047, 95% CI = 1.031-1.063, p < 0.01). The area under the ROC curve (AUC) for the LAP index was higher than that for WC and BMI. CONCLUSION: A high LAP index is associated with an increased risk of MCI in T2D patients. The LAP index appears to be a good indicator of risk of MCI in patients with T2D.


Assuntos
Disfunção Cognitiva/sangue , Disfunção Cognitiva/psicologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/psicologia , Produto da Acumulação Lipídica/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/diagnóstico , Estudos Transversais , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Triglicerídeos/sangue , Circunferência da Cintura/fisiologia
9.
Bioorg Med Chem Lett ; 30(20): 127419, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32768648

RESUMO

Discovery of novel classes of Gram-negative antibiotics with activity against multi-drug resistant infections is a critical unmet need. As an essential member of the lipoprotein biosynthetic pathway, lipoprotein signal peptidase II (LspA) is an attractive target for antibacterial drug discovery, with the natural product inhibitor globomycin offering a modestly-active starting point. Informed by structure-based design, the globomycin depsipeptide was optimized to improve activity against E. coli. Backbone modifications, together with adjustment of physicochemical properties, afforded potent compounds with good in vivo pharmacokinetic profiles. Optimized compounds such as 51 (E. coli MIC 3.1 µM) and 61 (E. coli MIC 0.78 µM) demonstrate broad spectrum activity against gram-negative pathogens and may provide opportunities for future antibiotic discovery.


Assuntos
Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Peptídeos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Peptídeos/síntese química , Peptídeos/química , Relação Estrutura-Atividade
10.
Mech Ageing Dev ; 190: 111294, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32585235

RESUMO

Type 2 diabetes mellitus (T2DM) is a global disease that poses a significant threat to public health. The incidence of both diabetes and dementia has increased simultaneously. Researchers have found that a large proportion of dementia patients have T2DM. In recent years, increasing evidence has demonstrated a link between cognitive decline and T2DM. Although the exact pathogenesis of cognitive impairment in T2DM is still unknown, current studies suggest that hyperglycemia, cerebrovascular disease, brain insulin resistance, and changes in γ-aminobutyric acid (GABAergic) neurons may mediate the association between T2DM and cognitive impairment. These potential mechanisms may become targets for the treatment of cognitive disorders in patients with T2DM. Glucagon-like peptide-1 (GLP-1), a widely used anti-diabetic drug, has been shown to not only effectively lower blood glucose but also improve neurological function. Previous research has confirmed that GLP-1 and its analogues are effective in the treatment of cognitive impairment in patients with T2DM. This review describes current evidence on the mechanisms underlying the association between T2DM and cognitive impairment. In particular, this review focuses on recent advances in GLP-1 and its analogues for the treatment of T2DM-related cognitive impairment.


Assuntos
Disfunção Cognitiva , Diabetes Mellitus Tipo 2 , Peptídeo 1 Semelhante ao Glucagon , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/fisiopatologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/psicologia , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Humanos , Incretinas/farmacologia
11.
Pharmacol Res ; 159: 104924, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32464323

RESUMO

Diabetic retinopathy (DR) is a serious condition that can cause blindness in diabetic patients. It is a neurovascular disease, but the pathogenesis leading to the onset of this disease is still not completely understood. However, hypoxia with subsequent neovascularization is a characteristic phenomenon observed with DR. Cellular response to hypoxia is mediated by the transcriptional regulator hypoxia-inducible factor (HIF). Long-term research has shown that one isotype of HIF, HIF-1α, may play a pivotal role under hypoxic conditions, and an increasing number of studies have shown that HIF-1α and its target genes contribute to retinal neovascularization. Therefore, targeting HIF-1α may lead to more effective DR treatments. This review describes the possible mechanisms of HIF-1α in neovascularization of DR. Furthermore, various inhibitors of HIF-1α that may have viable potential in the treatment of DR are also discussed.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Retinopatia Diabética/tratamento farmacológico , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Neovascularização Patológica , Inibidores da Angiogênese/efeitos adversos , Animais , Retinopatia Diabética/genética , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Regulação da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Conformação Proteica , Transdução de Sinais , Relação Estrutura-Atividade , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo
12.
Diabetes Metab Syndr Obes ; 13: 1359-1365, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32425568

RESUMO

Purpose: Diabetic retinopathy (DR) can increase the risk of mild cognitive impairment (MCI), which has been confirmed by previous researches. With the frequent occurrence of MCI in patients with DR, the early detection of MCI has become a research hot-spot. The aim of this study was to investigate the relationship between neuron-specific enolase (NSE) and MCI in patients with DR. Patients and Methods: A total of 124 patients with DR, including 56 MCI patients and 68 normal cognition patients, were recruited in this cross-sectional study. The demographic and clinical data of patients were collected through questionnaires. Serum NSE was measured using electrochemiluminescence immunoassay. The Minimum Mental State Examination (MMSE) scale was used to evaluate the cognitive function of the participants. Results: Compared with the normal cognition group, serum NSE levels and HbA1c levels in the MCI group were higher, while MMSE scores and educational level were lower (P<0.05). Serum NSE levels were significantly negatively correlated with MMSE total score, attention and calculation score, and language score (P<0.05). After adjusting for confounding factors, serum NSE still increased the MCI risk in DR patients (OR:1.606, 95CI%:1.264-2.041, P<0.001). The areas under the receiver operating characteristics (ROC) curves (AUC) of the crude model and the adjusted model were 0.75 and 0.73, respectively. Conclusion: A high serum NSE level is an independent risk factor for MCI in DR patients. In addition, serum NSE is expected to be a potential biomarker in DR patients with MCI.

13.
J Diabetes Res ; 2020: 6086780, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32190700

RESUMO

Background: Diabetic retinopathy (DR) is a severe complication of diabetes mellitus. DR is considered as a neurovascular disease. Retinal ganglion cell (RGC) loss plays an important role in the vision function disorder of diabetic patients. Histone deacetylase3 (HDAC3) is closely related to injury repair and nerve regeneration. The correlation between HDAC3 and retinal ganglion cells in diabetic retinopathy is still unclear yet. Methods: To investigate the chronological sequence of the abnormalities of retinal ganglion cells in diabetic retinopathy, we choose 15 male db/db mice (aged 8 weeks, 12 weeks, 16 weeks, 18 weeks, and 25 weeks; each group had 3 mice) as diabetic groups and 3 male db/m mice (aged 8 weeks) as the control group. In this study, we examined the morphological and immunohistochemical changes of HDAC3, Caspase3, and LC3B in a sequential manner by characterizing the process of retinal ganglion cell variation. Results: Blood glucose levels and body weights of db/db mice were significantly higher than that of the control group, P < 0.01. Compared with the control group, the number of retinal ganglion cells decreased with the duration of disease increasing. HDAC3 expression gradually increased in RGCs of db/db mice. Caspase3 expression gradually accelerated in RGCs of db/db mice. LC3B expression dynamically changed in RGCs of db/db mice. HDAC3 was positively correlated with Caspase3 expression (r = 0.7424), P < 0.01. Compared with the control group, the number of retinal ganglion cells decreased with the duration of disease increasing. HDAC3 expression gradually increased in RGCs of db/db mice. Caspase3 expression gradually accelerated in RGCs of db/db mice. LC3B expression dynamically changed in RGCs of db/db mice. HDAC3 was positively correlated with Caspase3 expression (r = 0.7424), P < 0.01. Compared with the control group, the number of retinal ganglion cells decreased with the duration of disease increasing. HDAC3 expression gradually increased in RGCs of db/db mice. Caspase3 expression gradually accelerated in RGCs of db/db mice. LC3B expression dynamically changed in RGCs of db/db mice. HDAC3 was positively correlated with Caspase3 expression (Discussion. We clarified the dynamic expression changes of HDAC3, Caspase3, and LC3B in retinal ganglion cells of db/db mice. Our results suggest the HDAC3 expression has a positive correlation with apoptosis and autophagy.


Assuntos
Apoptose/fisiologia , Autofagia/fisiologia , Retinopatia Diabética/metabolismo , Histona Desacetilases/metabolismo , Células Ganglionares da Retina/metabolismo , Animais , Caspase 3/metabolismo , Retinopatia Diabética/genética , Retinopatia Diabética/patologia , Histona Desacetilases/genética , Masculino , Camundongos , Células Ganglionares da Retina/patologia
14.
Horm Metab Res ; 52(3): 142-148, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32215885

RESUMO

Diabetic retinopathy (DR), a serious microvascular complication of diabetes, is a leading cause of blindness in adults. The pathogenesis of DR involves a variety of tissues and complex mechanisms, such as inflammation, oxidative stress, optic neurodegeneration, and autophagy. Nowadays, microRNAs (miRNAs), a novel group of non-coding small RNAs, have been extensively studied and recognized to play a key role in the pathogenesis of DR through aforementioned pathways. Furthermore, some miRNAs have been proposed as biomarkers that may be utilized to screen for DR. Also, miRNAs are a new therapy for DR. In this review, we summarize several miRNAs and, their roles in the pathogenesis of DR. miRNAs, as potential pharmacological targets for the diabetic retinopathy, may provide new insights for the treatment of DR.


Assuntos
Retinopatia Diabética/genética , MicroRNAs/genética , Animais , Biomarcadores/metabolismo , Retinopatia Diabética/metabolismo , Retinopatia Diabética/terapia , Humanos , MicroRNAs/metabolismo , Estresse Oxidativo
15.
Science ; 367(6480)2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-32079747

RESUMO

Current influenza vaccines only confer protection against homologous viruses. We synthesized pulmonary surfactant (PS)-biomimetic liposomes encapsulating 2',3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), an agonist of the interferon gene inducer STING (stimulator of interferon genes). The adjuvant (PS-GAMP) vigorously augmented influenza vaccine-induced humoral and CD8+ T cell immune responses in mice by simulating the early phase of viral infection without concomitant excess inflammation. Two days after intranasal immunization with PS-GAMP-adjuvanted H1N1 vaccine, strong cross-protection was elicited against distant H1N1 and heterosubtypic H3N2, H5N1, and H7N9 viruses for at least 6 months while maintaining lung-resident memory CD8+ T cells. Adjuvanticity was then validated in ferrets. When alveolar epithelial cells (AECs) lacked Sting or gap junctions were blocked, PS-GAMP-mediated adjuvanticity was substantially abrogated in vivo. Thus, AECs play a pivotal role in configuring heterosubtypic immunity.


Assuntos
Materiais Biomiméticos , Vacinas contra Influenza/imunologia , Nanopartículas , Nucleotídeos Cíclicos/administração & dosagem , Infecções por Orthomyxoviridae/prevenção & controle , Surfactantes Pulmonares/imunologia , Vacinação/métodos , Adjuvantes Imunológicos/administração & dosagem , Administração Intranasal , Animais , Materiais Biomiméticos/administração & dosagem , Linfócitos T CD8-Positivos/imunologia , Furões , Memória Imunológica , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Virus da Influenza A Subtipo H5N1/imunologia , Subtipo H7N9 do Vírus da Influenza A/imunologia , Vacinas contra Influenza/administração & dosagem , Lipossomos , Proteínas de Membrana/agonistas , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Nanopartículas/administração & dosagem , Nucleotídeos Cíclicos/farmacologia , Surfactantes Pulmonares/administração & dosagem
16.
Life Sci ; 240: 117138, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31809715

RESUMO

Pyroptosis is a form of cell death mediated by gasdermin D (GSDMD); it is characterised by NLRP3 inflammasome activation, caspase activation, cell membrane pore formation, and the release of interleukin-1ß and interleukin-18. NLRP3 inflammasome activation plays a central role in pyroptosis. Recent research has suggested that NLRP3 inflammasome activation may be involved in the occurrence and development of diabetes mellitus and its associated complications. This finding provided the impetus for us to clarify the significance of pyroptosis in diabetes. In this review, we summarise the current understanding of the molecular mechanisms involved in pyroptosis, as well as recent advances in the role of NLRP3 inflammasome activation and pyroptosis in the development of diabetes and diabetic complications.


Assuntos
Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/genética , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/genética , Inflamassomos/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Piroptose/genética , Animais , Complicações do Diabetes/patologia , Diabetes Mellitus/patologia , Humanos , Inflamassomos/efeitos dos fármacos , Piroptose/efeitos dos fármacos
17.
Brain ; 142(9): 2845-2859, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31312839

RESUMO

Mutations in lysosomal genes increase the risk of neurodegenerative diseases, as is the case for Parkinson's disease. Here, we found that pathogenic and protective mutations in arylsulfatase A (ARSA), a gene responsible for metachromatic leukodystrophy, a lysosomal storage disorder, are linked to Parkinson's disease. Plasma ARSA protein levels were changed in Parkinson's disease patients. ARSA deficiency caused increases in α-synuclein aggregation and secretion, and increases in α-synuclein propagation in cells and nematodes. Despite being a lysosomal protein, ARSA directly interacts with α-synuclein in the cytosol. The interaction was more extensive with protective ARSA variant and less with pathogenic ARSA variant than wild-type. ARSA inhibited the in vitro fibrillation of α-synuclein in a dose-dependent manner. Ectopic expression of ARSA reversed the α-synuclein phenotypes in both cell and fly models of synucleinopathy, the effects correlating with the extent of the physical interaction between these molecules. Collectively, these results suggest that ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein.


Assuntos
Cerebrosídeo Sulfatase/fisiologia , Chaperonas Moleculares/metabolismo , Mutação de Sentido Incorreto , Doença de Parkinson/metabolismo , Mutação Puntual , alfa-Sinucleína/metabolismo , Adulto , Idoso , Animais , Animais Geneticamente Modificados , Encéfalo/enzimologia , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Células Cultivadas , Cerebrosídeo Sulfatase/sangue , Cerebrosídeo Sulfatase/genética , Demência/sangue , Demência/etiologia , Proteínas de Drosophila/deficiência , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Feminino , Técnicas de Inativação de Genes , Genes Dominantes , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/genética , Doença de Parkinson/psicologia , Linhagem , Agregação Patológica de Proteínas/genética , Mapeamento de Interação de Proteínas , Proteínas Recombinantes/metabolismo
18.
Inflammation ; 42(5): 1808-1820, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31243649

RESUMO

Hyaluronan (HA) fragments have been proposed to elicit defensive or pro-inflammatory responses in many cell types. For articular chondrocytes in an inflammatory environment, studies have failed to reach consensus on the endogenous production or effects of added HA fragments. The present study was undertaken to resolve this discrepancy. Cultured primary human articular chondrocytes were exposed to the inflammatory cytokine IL-1ß, and then tested for changes in HA content/size in conditioned medium, and for the expression of genes important in HA binding/signaling or metabolism, and in other catabolic/anabolic responses. Changes in gene expression caused by enzymatic degradation of endogenous HA, or addition of exogenous HA fragments, were examined. IL-1ß increased the mRNA levels for HA synthases HAS2/HAS3 and for the HA-binding proteins CD44 and TSG-6. mRNA levels for TLR4 and RHAMM were very low and were little affected by IL-1ß. mRNA levels for catabolic markers were increased, while type II collagen (α1(II)) and aggrecan were decreased. HA concentration in the conditioned medium was increased, but the HA was not degraded. Treatment with recombinant hyaluronidase or addition of low endotoxin HA fragments did not elicit pro-inflammatory responses. Our findings showed that HA fragments were not produced by IL-1ß-stimulated human articular chondrocytes in the absence of other sources of reactive oxygen or nitrogen species, and that exogenous HA fragments from oligosaccharides up to about 40 kDa in molecular mass were not pro-inflammatory agents for human articular chondrocytes, probably due to low expression of TLR4 and RHAMM in these cells.


Assuntos
Cartilagem Articular/citologia , Condrócitos/efeitos dos fármacos , Ácido Hialurônico/farmacologia , Inflamação/etiologia , Células Cultivadas , Condrócitos/citologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Receptores de Hialuronatos/metabolismo , Fragmentos de Peptídeos/farmacologia
19.
J Environ Manage ; 241: 53-58, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30981143

RESUMO

Phenol as a semi-volatile organic compound (SVOC) extensively presents in industrial wastewater. Moreover, it is a main compound of tar existing in the vapor phase from biomass pyrolysis or gasification. So far, most of works on the phenol adsorption by activated carbons have been conducted in the liquid phase. However, the adsorption of phenol in the gas phase has not been reported. This work aims to synthesize the hierarchically porous carbons from the unaltered and pelletized rice husk (RH) via a facile pyrolysis followed by the ball-milling-assisted KOH activation. Herein, the silica nanoparticles in RH acted as a self-template to remarkably increase specific surface areas and pores, thereby giving rise to the formation of hierarchically porous carbons, which showed a relatively high adsorption capacity (maximum value: 1919 mg/g) of phenol in the vapor phase. Generally, the process of phenol adsorption onto porous carbons in the gas phase followed with various interactions, including pore filling, electrostatic interaction, hydrophobic effect, and functional groups effect (e.g., π-π interaction). And the pseudo-second-order model could well describe the adsorption kinetic. It is noted that the pelletized RH was more favorable to develop the porous carbons with the hierarchically meso-microporous structures that could enhance the transfer of the phenol molecules via the outer layer and subsequent uptake by the adsorption sites on the inner layer. Further, the SVOC phenol was hard to volatilize under ambient conditions due to its relatively higher boiling point (181.7 °C), so the thermal desorption was a potential way to regenerate the spent activated biochars.


Assuntos
Oryza , Fenol , Adsorção , Fenóis , Porosidade
20.
Cell Mol Immunol ; 16(9): 757-769, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30705387

RESUMO

Proper control of B cell growth and metabolism is crucial for B-cell-mediated immunity, but the underlying molecular mechanisms remain incompletely understood. In this study, Sin1, a key component of mTOR complex 2 (mTORC2), specifically regulates B cell growth and metabolism. Genetic ablation of Sin1 in B cells reduces the cell size at either the transitional stage or upon antigen stimulation and severely impairs metabolism. Sin1 deficiency also severely impairs B-cell proliferation, antibody responses, and anti-viral immunity. At the molecular level, Sin1 controls the expression and stability of the c-Myc protein and maintains the activity of mTORC1 through the Akt-dependent inactivation of GSK3 and TSC1/2, respectively. Therefore, our study reveals a novel and specific role for Sin1 in coordinating the activation of mTORC2 and mTORC1 to control B cell growth and metabolism.


Assuntos
Linfócitos B/citologia , Linfócitos B/metabolismo , Proteínas de Transporte/fisiologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Animais , Linfócitos B/imunologia , Proliferação de Células , Células Cultivadas , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 2 de Rapamicina/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Proteínas Proto-Oncogênicas c-myc/genética , Transdução de Sinais
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